In this study, the mechanism involved in the anoretic effect of d-fenfluramine and CM 57 277 was investigated. Repeated injections of these two anorectic drugs resulted in an elevation of hypothalamic met5-and beta-endorphin. This increase is associated with a reduction in body weight. The effect of these two anorectics can be reversed by metergoline, a serotonin receptor antagonist. The results suggest that a decreased utilization of hypothalamic opioid peptides caused by a facilitation of serotonergic transmission may be responsible for the anorectic action of fenfluramine and CM 57 277 but not that of amphetamine. Met5-enkephalin release was also investigated in this study. The interaction between serotonergic and endogenous opioid systems and the importance of endogenous opioid peptides in eating behavior are well demonstrated in this study. These findings may sharpen our understanding of normal eating behavior. The interactions of met5-enkephalin, other transmitters, and substance P, was also investigated in this study. Met5-enkephalin can be released from periaqueductal gray slices by substance P suggesting that substance P analgesia may be mediated by opioid peptides.